Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2010;469:539–42.Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2010;19:17–30.An increasing number of cancer genomes have been sequenced, with many of these sequences leading to only incrementally improved understanding of mutational drivers for specific cancers. Breaking this trend, a recent article by researchers from the Wellcome Trust Sanger Institute identified mutations in PBRM1 as being truncated in 41% of 227 cases of renal cell carcinoma. This gene, part of the SWI/SNF chromatin remodeling complex, complements mutations found earlier by the same group (in a report that did not mention PBRM1) identifying inactivating mutations in UTX, JARID1C, and SETD2 (collectively found in approximately 15% of cases, and modifying the repressing H3K27 modification). These studies link mutation in histone and chromatin modifying enzymes to the pathogenesis of renal cell cancer. Interestingly, mutations in genes that globally affect chromatin-modifying enzymes have also been described in acute myeloid leukemia (AML) and glioblastoma tumors driven by gain of function in isocitrate dehydrogenase 1 and 2. Xu and colleagues have demonstrated that 2-hydroxyglutarate, the abnormal metabolite produced by IDH mutant tumors, is a competitive inhibitor of multiple α-ketoglutarate-dependent enzymes (α-ketoglutarate being the normal product of IDH), including histone demethylases and 5-methylcytosine hydroxylases. Thus, subgroups of glioma, AML, and renal cell cancer are driven by mutational dysregulation of genes controlling epigenetic modification.Powell AE, Anderson EC, Davies PS, Silk AD, Pelz C, Impey S, et al. Fusion between intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res 2011;71:1497–505.The idea that cancer cells undergo cellular fusion is an old concept that has not been widely incorporated into current thinking about tumorigenesis. Evidence that cancer cells can undergo homotypic cellular fusion is clear; however, the idea that cancer cells can co-opt cellular properties through fusion with normal cells is more controversial. These researchers have previously reported that epithelial cells and blood cells can undergo cellular fusion. Now, Powell and colleagues have provided evidence that intestinal cells and macrophages can undergo cellular fusion, resulting in nuclear reprogramming that contributes to their malignant properties, including immune evasion. These extraordinary results suggest the possibility that cancer cells can evade immune detection by literally incorporating the genomes of immune regulatory cells.Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer Res 2011;71:645–54.MicroRNAs (miRNA) play fundamental roles in tumor progression, functioning as oncogenes or tumor suppressor genes. Several miRNAs are differentially expressed in normal mammary gland as compared with breast carcinoma tissue; however, the roles of specific miRNAs in brain metastatic breast cancer (BMBC) remain unclear. BMBC is characterized by overexpression of heparanase (HPSE), which is a potent protumorigenic, proangiogenic, and prometastatic enzyme. In a recent report from Zhang and colleagues, the hypothesis that HSPE gene expression might be regulated by specific miRNAs, and thus be a therapeutic anticancer target, was evaluated. miRanda and RNA hybrid miR-1258 were identified as putative genetic elements that directly target HPSE and suppress BMBC. An inverse correlation was found between miR-1258 levels and HPSE expression, enzymatic activity, and metastatic properties. Levels of miR-1258 were lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. Moreover, this relationship was supported using paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. Expression of miR-1259 inhibited HPSE expression and activity in BMBC, whereas HPSE expression blocked the phenotypic changes induced by miRNA-1258. Stable expression of miR-1258 in BMBC cells inhibited HPSE in vitro cell invasion and experimental brain metastasis. This interesting study supports a direct link between miR-1258 and HPSE expression in mediating brain metastatic breast cancer, suggesting the potential utility of heparanase-based therapeutics for treating patients with brain metastasesSmith BH, Gazda LS, Conn BL, Jain K, Asina S, Levine DM, et al. Three-dimensional culture of mouse renal carcinoma cells in agarose macrobeads selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. Cancer Res 2011:71:716-724.Standard 2-dimensional cell cultures are limited in their ability to precisely recreate the in vivo tumor environment. In this context, use of 3-dimensional culture systems is a more appropriate mimic of the in vivo tumor environment because cells are well organized with consistent shape and morphology and reflect cell-cell and cell-matrix interactions observed in vivo. Smith and colleagues have examined the effect of encapsulating and maintaining viable and functional pancreatic islets in agarose-agarose macrobeads (diameter, 6–8 mm) as a unique way to culture tumor cell lines. Approximately 1% of mouse renal adenocarcinoma cells grown in the macrobeads over several months form discrete elliptical colonies as tumor cell niches with increasing metabolic activity in parallel to colony size. BrdU incorporation and activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling indicated that the tumor colonies continue to undergo cell turnover. Growth under macrobead conditions likely results in changes in gene expression, including expression of SCA-1 and Oct4, as well as upregulation of stem cell-like genes, such as those associated with the Wnt pathway. These findings suggest that the macrobeads select for a subpopulation of cells with cancer stem cell or cancer progenitor properties and provide further support for growing tumor cells in an environment that may be more compatible and reflective of growth in vivo.Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow derived myofibroblasts contribute to the mesenchymal stem cell niche, and promote tumor growth. Cancer Cell 2011;19:257–72.The tumor stroma contributes to malignant progression in cancer, with clear roles demonstrated for mononuclear cells and macrophages. Quante and colleagues have analyzed cancer-associated fibroblasts (CAF) in mouse models of gastric cancer, induced by infection with Helicobacter organisms. Bacterial infection in these mice led to inflammation and dysplasia and was associated with expansion and recruitment of a subpopulation of CAFs derived from mesenchymal stem cells, which reside in bone marrow. Recruitment of CAFs was dependent on signaling through TGFβ and SDF-1α and contributed to frank tumor formation in Helicobacter-infected animals. Thus, homing and expansion of a bone marrow-derived population of CAFs contributes to tumor growth in mouse models of inflammation-induced gastric cancerTang YC, Williams BR, Siegel JJ, Amon A. Identification of aneuploidy-selective antiproliferation compounds. Cell 2011;144:499–512.The ability to turn markers of malignant aggressiveness into therapeutic targets has driven a number of effective therapies in cancer, with examples including highly aggressive childhood leukemias, many of which are highly proliferative, and therefore susceptible to standard chemotherapy. In addition, expression of aggressive cancer drivers, including BCR-Abl, HER2, and kinase-activating mutations of EGFR, endows cancers with susceptibility to therapies that target respective oncogenic lesions. The systematic screen for such synthetic lethal combinations has subsequently led to identification of PARP inhibitors that exhibit unique activity in BRCA-mutant breast cancers. Tang and colleagues screened aneuploid fibroblasts for vulnerability to agents inducing genotoxic, proteotic, or energy stress and identified AICAR (which induces energy stress) and 17-AAG (which induces proteotic stress) as candidate compounds. AICAR induced p53-dependent apoptosis in aneuploid mouse embryo fibroblasts, while both agents exhibited activity in aneuploid, but not euploid mouse embryo fibroblasts, in aneuploidy cancer cell lines, and in aneuploid, but not near-euploid human colorectal cancer xenografts. These results indicate that aneuploidy may represent a marker of selective vulnerability to specific anticancer agents.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.